In recent years, calcineurin inhibitors such as ciclosporin and FK506 have been used to prevent rejection of patients who underwent organ transplantation. However, a certain kind of calcineurin inhibitor like ciclosporin sometimes causes adverse side effects such as nephrotoxicity, hepatotoxicity, neurotoxicity and the like. In an attempt to prevent rejection in transplant patients, therefore, the development of a safer and more effective pharmaceutical agent is ongoing.
Patent references 1-3 disclose 2-aminopropane-1,3-diol compounds useful as agents for preventing (acute or chronic) rejection in organ or bone marrow transplantation, or therapeutic drugs for various autoimmune diseases such as psoriasis, Behcet's disease and the like and rheumatic affection.
One of such compounds, 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride (hereinafter sometimes to be abbreviated as FTY720) is a compound currently under clinical development as an agent for preventing rejection in renal transplantation. FTY720 is rapidly converted by sphingosine kinase into phosphorylated FTY720 [hereinafter sometimes to be referred to as FTY720-P, e.g., (±)2-amino-2-phosphoryloxymethyl-4-(4-octylphenyl)butanol] in the body. FTY720-P acts as an agonist on 4 kinds of sphingosine-1-phosphate (hereinafter sometimes to be referred to as S1P) receptors (other than S1P2) out of 5 kinds of S1P receptors (hereinafter sometimes to be referred to as S1P1-5, respectively) (non-patent reference 1).
Recently, it has been reported that S1P1 out of the S1P receptors is essential for the transfer of mature lymphocytes from the thymus and secondary lymphoid tissues. FTY720-P down regulates S1P1 on lymphocytes by acting as an S1P1 agonist. Consequently, it is suggested that transfer of mature lymphocytes from the thymus and secondary lymphoid tissues is inhibited, and circulating mature lymphocytes in the blood are isolated in the secondary lymphoid tissues, whereby an immunosuppressive action is exerted (non-patent reference 2).
On the other hand, conventional 2-aminopropane-1,3-diol compounds are feared to cause side effects of transient bradycardia expression. To solve the problem, many novel compounds obtained by chemical structural modification of 2-aminopropane-1,3-diol compounds have been reported. Among those, as a compound having a biaryl structure in the hydrophobic carbon chain FTY720 has, patent reference 4 discloses a biaryl compound having substituent(s) as an S1P receptor modulator. In addition, patent reference 5 discloses a biaryl compound having a certain kind of substituent, which is useful as an immunosuppressant. However, they do not disclose arylthio, aryloxy, arylcarbonyl, arylamino and the like as the substituents possessed by the biaryl structure. In any case, they have not reached a satisfactory level regarding the safety of a pharmaceutical product.    patent reference 1: WO94/08943    patent reference 2: WO96/06068    patent reference 3: WO98/45429    patent reference 4: WO03/099192    patent reference 5: JP-A-2004-307440    non-patent reference 1: Science, 2002, No. 296, pp. 346-349    non-patent reference 2: Nature, 2004, No. 427, pp. 355-360